Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

• the present invention relates to stabilized formulations of blended
• preservative systems comprising isothiazolone, a formaldehyde donor, a stabilizer for
• DDMH l,3-dimethylol-5,5-dimethylhydantoin
• compositions which contain very low amounts of free formaldehyde. (See U.S. Patent 5,405,862.)
• governmental regulations currently demand low free formaldehyde products.
• compositions can be preserved using isothiazolones and DMDMH
• Isothiazolone has never been pre-mixed with a formaldehyde donor in a stabilized mixture, such that the isothiazolone retains its activity as a preservative for any significant period of time, before adding these active components to
• Isothiazolone is highly toxic and very unstable under most circumstances, such as when present in water or other reactive molecule.
• To make the compound stable large amounts of cationic salts are added and the isothiazolone is diluted (usually to about 14% or less). While under these conditions, isothiazolone is stable at room temperature at low pH (from 1-4). During storage and manufacturing conditions the temperature and pH
• isothiazolone may increase causing isothiazolone to become unstable. While highly useful for controlling bacteria, fungi and other contaminating microbes in end-use products, isothiazolone's instability under less than ideal conditions results in a marked loss of
• isothiazolone which is stable at a broad range of temperature and pH.
• a highly stable, preservative formulation having broad spectrum biocidal activity can be prepared by admixing one or more isothiazolones with a formaldehyde donor, such as alkanol-substituted dimethylhydantoins, and a hydantoin as a stabilizer for isothiazolone.
• a formaldehyde donor such as alkanol-substituted dimethylhydantoins
• the stabilized formulations retain their stability at less acidic pH levels and high temperature.
• the pH of the preservative formulation may be adjusted to pH 4-8 as
• a preservative system of the invention will withstand the high temperatures encountered during manufacturing or in warehouse environments. Moreover, high levels
• the preservative systems of the invention are especially useful in personal care products, such as shampoos, cosmetics, creams, lotions, and liquid soaps, which have a more neutral pH range (5-7), and remain stable at room and higher temperatures in the
• preservative systems of the invention comply with emerging government regulations, since they have low amounts of free formaldehyde, i.e., less than 0.2%.
• a highly stable isothiazolone- containing preservative permits use of less active component, and thus provides a nontoxic, highly effective preservative formulation.
• a stabilized preservative system can be more cost-effective, both to the manufacturer and the end user, while providing non-irritating formulations when added to personal care products.
• the invention further provides methods for reducing or inhibiting the growth of microbes in personal care, household, or industrial products by incorporating the stabilized preservative systems of the invention.
• a first active component of the stabilized preservative system of the invention comprises one or more 3-isothiazolones having formula I:
• X is hydrogen or halogen, preferably chlorine, and R is an alkyl chain of from 1 to
• isothiazolone components include 5-chloro-2-methyl-4- isothiazolin-3-one (CMI) and 2-methyl-4-isothiazolin-3-one (MI), and mixtures thereof (e.g., CMI/MI).
• CMI 5-chloro-2-methyl-4- isothiazolin-3-one
• MI 2-methyl-4-isothiazolin-3-one
• 3-isothiazolones can be used in the invention, including 4-chloro-2-methyl-4-isothiazolin-3-one, dichloroisothiazolones such as 4,5-dichloro-2-methyl-4-isothiazolin-3-one, bromoisothiazolones such as 5-bromo-2-methyl-4-isothiazolin-3-one, n-octylisothiazolones such as 2-n-octyl-4- isothiazolin-3-one, and benzisothiazolone.
• a second active component of the stabilized preservative system of the invention is a formaldehyde donor, such as hydantoins, N,N"-methylene-bis[N'- (hydroxymethyl)-2,5-dioxo-4-imidazolidinyl]urea, N'-(hydroxymethyl)-N-(l,3- dihydroxymethyl-2,5-dioxo-4-imidazolidinyl]-N'-(hydroxymethyl)urea, and Quaternium-
• Preferred compounds are alkanoldialkyl hydantoins having formula II:
• R_ and R 2 are each independently hydrogen or (CH 2 )OH, with the proviso that both R, and R 2 cannot be hydrogen, and R 3 and R 4 are each independently hydrogen, a methyl group, an ethyl group, a propyl group, or an aryl group.
• Alkanol-substituted dimethylhydantoin compounds are preferably used.
• formaldehyde donors include n-hydroxymethyl-ureas such as imidazolinyl urea and diazolidinyl urea, diaminomethanes, 1 ,3-oxazolidines, quaternary hexaminium salts such as Quaternium 15, C-methylols, such as Bronopol, 2-
• Stabilizers used in the present invention include hydantoins, ureas and derivatives thereof.
• the hydantoins are represented by formula III:
• R_ to R 4 are independently selected from H, and a C, to C 22 alkyl group.
• R, to R 5 are independently selected from H or C, to C 22 .
• R, to R 7 are independently selected from H, CH 3 , C 2 H 5 or C 3 H 7 .
• R, to R 4 are independently selected from H or C, to C 12 . Where all the R groups are
• the compound is urea.
• the stabilizer is 5,5-dimethylhydantoin or methylethylhydantoin
• Water is the preferred solvent for use in the present invention.
• solvent for use in the present invention.
• a hydroxyl solvent can be used which includes mono-, di-, and polyhydroxyl alcohols.
• monohydroxyl alcohols having from about 1 to 5 carbon atoms, most preferably ethanol and propanol, may be used.
• Dihydroxyl alcohols e.g., glycols
• C 2 to C 8 diols e.g., propylene glycol and butylene glycol
• Other compounds which can be used include dipropylene glycol, glycerin, diglycerin, PPG-9, PPG-2-buteth- 2, butoxypropanol, butoxydiglycol, PPG-2 butyl ether, glycereth-7, sorbitol, isopentyldiol, myristyl myristate, and phenoxy ethanol.
• Table 1 provides ranges for the broad spectrum stabilized formaldehyde donor/isothiazolone preservative concentrates of the invention.
• the ratio of the formaldehyde donor to isothiazolone compound for the broad spectrum concentrate may broadly be from about 5000:1 to 1 :1, preferably from
• the ratio of the total stabilizer to the isothiazolone compound in the above concentrate may broadly be from about 1:1 to 2000:1, preferably from about 50:1 to
• This formulation has a free formaldehyde concentration of less than 1 wt.%, preferably less than 0.2 wt.%.
• Total formaldehyde concentration is from 5 wt.% to 25 wt.%, and preferably from 12 wt.% to 17 wt.%.
• a preferred alkanoldialkylhydantoin is l,3-dimethylol-5,5- dimethylhydantoin (DMDMH), and may be obtained conveniently in a mixture such as Glydant II (Lonza, Inc., Fair Lawn, NJ), which contains 70% solids (65% DMDMH, 30% monomethyldimethylhydantoin (MMDMH), and 5% dimethylhydantoin (DMH)) and the remainder is water.
• Glydant II has a total formaldehyde content of 17%.
• preservative concentrates of the invention can be readily prepared in accordance with procedures well known to those skilled in the art, simply by mixing the components set forth in Table 1 , supra, and adjusting the pH using any organic or mineral acid (e.g., hydrochloric acid and acetic acid) suitable for the user's purpose.
• organic or mineral acid e.g., hydrochloric acid and acetic acid
• the concentration of the active compounds in the use-dilution depends on the nature of the microorganisms to be combated and the composition of the final product
• the optimum amount of preservative to use for preserving an aqueous composition can be determined by means of screening tests known in the art, and in accordance with the formulation ranges provided in Tables 1 and 2.
• the use level is generally 0.00005 to 5% by weight
• Preservative formulations of the invention can also be used directly as they are manufactured without dilution, or in any other manner traditionally used in manufacturing, such as by metering.
• the stabilizer may be combined
• composition can be used in making the preservative formulation of the invention by mixing it with a formaldehyde donor.
• the stabilizer DMH also serves to minimize the amount of free formaldehyde.
• the amount of DMH typically present in formaldehyde donor compositions is not sufficient to
• the total alkyl hydantoin concentration must be considered in determining how much alkyl hydantoin should be added to stabilize the isothiazolone.
• the total alkyl hydantoin concentration is equal to free alkyl hydantoin plus reacted alkyl hydantoin (e.g. , the DMH in the condensation
• the “total" alkyl hydantoin concentration is different from the “added” alkyl hydantoin concentration. Since alkyl hydantoin (free and reacted) may be present in certain formaldehyde donor compositions, an amount of alkyl hydantoin may be added to
• a prepared formaldehyde donor composition e.g., Glydant II
• a prepared formaldehyde donor composition e.g., Glydant II
• Glydant II contains free and reacted alkyl hydantoin, such that the added alkyl hydantoin in combination with the alkylhydantoin in the formaldehyde donor composition provide a total alkyl hydantoin
• the preservative of the invention is useful for combating microorganisms
• products include any product that is applied to or contacted with the body of humans or
• dishwashing detergent automotive cleaner, surfactant solutions, household polishes,
• non-food fungicide for growing crops
• non-food fungicide non-food herbicide, non-food insecticide, non-food repellent, non-food biopesticide, anti-tarnish products
• pre-moistened sponges pre-moistened mops
• coatings polymer emulsion, natural latex
• mineral slurries mineral slurries, pigment slurries, water-based building compounds, caulk, sealer, metal
• hydrocarbon fuels industrial recirculating cooling water, lubricants, and other materials which can be attacked or decomposed by microorganisms.
• Microorganisms which effect contamination or degradation of an aqueous product include bacteria, fungi, yeasts, algae, and slime.
• Microorganisms of the following genera are examples: Alternaria, such as Alternaria tenuis, Aspergillus, such as Aspergillus niger, Chaetomium, such as Chaetomium globosum, Candida, such as
• Penicillium such as Penicillium
• Trichophyton such as Trichophyton mentagrophytes
• Aureobasidium such as
• Aureobasidium pullulans Enterobacter, such as Enterobacter gergoviae, Trichoderma, such as Trichoderma viride, Escherichia, such as Escherichia coli, Pseudomonas, such as Pseudomonas aeruginosa and Burkholderia cepacia, and Staphylococcus, such as
• Staphylococcus aureus and Staphylococcus epidermidis are Staphylococcus aureus and Staphylococcus epidermidis.
• Isothiazolone was tested for stability under accelerated storage conditions and recovery thereof was compared to that of formulations maintained at room temperature (RT).
• Three test formulations were prepared by mixing 14% isothiazolone (CMI/MI 2.8:1) with Glydant II (Lonza, Inc., Fair Lawn, NJ), with or without adding a stabilizing amount of DMH, and adjusted to pHs of approximately 5.0, 5.5 and 6.0 using
• citric acid (CA) or HC1 A total of 9 formulations were prepared having a final
• the pH was about 5.0.
• the pH was about 5.5 and for tests 7-9, the pH was about 6.0.
• Margin of error for rates of recovery is ⁇ 2%. Where rate of recovery is greater than 100%, it was assumed that recovery of isothiazolone was 100%.
• Table 3 shows the effectiveness of 5,5-dimethylhydantoin as a stabilizer of
• test formulation no. 4 the recovery of unstabilized CMI at pH 5.5 (CA as pH adjuster), was 78% under accelerated conditions.
• test formulation no. 5 when a stabilizing amount of DMH was present, the recovery of
• the pH of the protein shampoo was adjusted to pH 7.0, and the pH preservative formulation was adjusted to a pH of 5.5 using HCl.
• the preservative formulation was prepared in accordance with the formulation of Table 2 (tests 3, 6 and 9).
• the formaldehyde donor composition was 35% DMDMH, 30% MMDMH, 5% DMH and 30% water "
• the Isothiazolone composition contained a conventional blend of 14% CMI/MI.
• Five protein shampoo test formulations were prepared and tested: one without the addition of the preservative formulation and four with varying amounts of the preservative formulation.
• the concentrations of protein shampoo and preservative used are:

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• 1999
  • 1999-05-11 US US09/309,686 patent/US6121302A/en not_active Expired - Fee Related
• 2000
  • 2000-05-05 BR BR0011516-9A patent/BR0011516A/pt not_active IP Right Cessation
  • 2000-05-05 AU AU49894/00A patent/AU4989400A/en not_active Abandoned
  • 2000-05-05 DK DK00932123T patent/DK1071330T3/da active
  • 2000-05-05 DE DE60000343T patent/DE60000343T2/de not_active Expired - Fee Related
  • 2000-05-05 ES ES00932123T patent/ES2182803T3/es not_active Expired - Lifetime
  • 2000-05-05 CA CA002372812A patent/CA2372812A1/en not_active Abandoned
  • 2000-05-05 WO PCT/US2000/012381 patent/WO2000067579A1/en active IP Right Grant
  • 2000-05-05 JP JP2000616625A patent/JP2002544144A/ja active Pending
  • 2000-05-05 AT AT00932123T patent/ATE222456T1/de not_active IP Right Cessation
  • 2000-05-05 EP EP00932123A patent/EP1071330B1/en not_active Expired - Lifetime
  • 2000-05-11 PE PE2000000439A patent/PE20010135A1/es not_active Application Discontinuation
  • 2000-05-11 CO CO00034035A patent/CO5170492A1/es not_active Application Discontinuation
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